Method and apparatus for measurement of cardiopulmonary function

ABSTRACT

A method for measuring anatomical dead space in a lung, the method comprising: (a) providing, in a supply of inspired gas, at least one indicator gas for inhalation by a patient during a test, the concentration of the indicator gas being controlled such as to follow a sinewave pattern over successive breaths; (b) measuring, over successive breaths, the flow rate and concentration of the indicator gas during both inspiration and exhalation of the patient; (c) fitting sinewave envelopes to the measured concentration values of the indicator gas over the successive breaths and, from the fitted sinewave envelopes, determining the inspired concentration, the mixed expired concentration, and the end expired concentration in respect of the indicator gas for each breath; and (d) calculating the anatomical dead space for each of a plurality of inspirations based on a conservation-of-mass principle. Also provided is a test apparatus for carrying out such a method, and a computer program or set of instruction code which, when executed, causes a processor to implement such a method.

FIELD OF THE INVENTION

The present invention relates to a method and associated apparatus fornon-invasively measuring aspects of cardiopulmonary function in asubject. For example, embodiments of the invention may be used fornon-invasively measuring one or more of anatomical dead space,functional residual capacity (FRC), pulmonary blood flow, and lunginhomogeneity.

BACKGROUND TO THE INVENTION

Dead space, functional residual capacity, pulmonary blood flow, and lunginhomogeneity are important parameters in relation to thecardiopulmonary condition of a patient. While there are methodsavailable using respired gases to measure these parameters individually,it is currently difficult or even impossible to simultaneously givemeasurements of dead space, FRC, pulmonary blood flow, and lunginhomogeneity, and to make these measurements continuously.

Dead space is the volume of air which is inhaled that does not take partin the gas exchange, either because it remains in the conductingairways, or reaches alveoli that are not perfused. Dead space is oftenmeasured using the Bohr equation for physiological dead space, orFowler's method for anatomical dead space. U.S. Pat. No. 6,599,252(Starr, 2003) describes a method and apparatus to determine anatomicaldead space using a sensor indicating volume and a gas analyser measuringconcentration of a gas such as CO₂ or O₂ in a patient's expiratory flow.

Functional residual capacity (FRC) is the volume of gas, includingcarbon dioxide, remaining within the lungs of a subject at the end ofpassive expiration. Common methods to measure FRC include bodyplethysmography, helium dilution, and gas wash-in/wash-out techniques.Such methods are described in the literature (West, 2008) and in EP0653183 (Larsson et al., 1999) and EP 1767235 (Choncholas et al., 2007),which describe adaptations of gas wash-in/wash-out techniques for usedin ventilated patients.

Pulmonary blood flow is the average total blood flow per unit time inpulmonary circulation. For non-invasive pulmonary blood flow measurementusing respired gases, a variety of indirect Fick techniques includingsingle breath and rebreathing have been proposed over the years. Only afew techniques are commercially available, such as the NovametrixNon-Invasive Cardiac Output (NICO) which uses CO₂ rebreathing technique,or the Innocor technique (US 2009/0320844 (Clemensen and Nielsen, 2009)and US 2011/0098589 (Clemensen and Nielsen, 2011) which uses N₂Orebreathing. However, a major disadvantage of rebreathing techniques isthat it requires a bag system and therefore cannot be used forventilated patients.

It is unfortunate that ventilated patients, who are the most in need ofmonitoring cardiopulmonary function, are the hardest group to test usingtraditional methods. The information regarding the cardiopulmonaryfunction is not only important to monitor how the ventilated patientsrecover over time, but is also useful to help choose appropriateventilator settings such as tidal volume and the positive end expiratorypressure (PEEP).

Lung inhomogeneity is another important parameter. However at present,only the lung clearance index, which is derived from a washout test, isan accepted technique to investigate ventilation-volume inhomogeneity.

No established technique exists to investigate ventilation-perfusioninhomogeneity using respired gases. No established technique exists tocombine the above-described methods to provide simultaneous informationon dead space, FRC, pulmonary blood flow, and lung inhomogeneity. It ispossible that the re-breathing techniques of others as described abovemight be adaptable to measure FRC and pulmonary blood flow, using aninert insoluble gas. The limitations of such a theoretical procedurehowever include the fact that it would not be possible to use forventilated patients.

There is accordingly a need for a method which will accurately providemeasurements of one or more of dead space, FRC, pulmonary blood flow,and lung inhomogeneity. There is a need for a method which can be usedto provide such measurements for a ventilated patient. There is a needfor a method which can be used non-invasively to provide suchmeasurements and for these measurements to be made continuously.

SUMMARY OF THE INVENTION

The present invention addresses one or more of the above needs byproviding an apparatus and method which permit the simultaneousmeasurement of the above cardiopulmonary parameters (dead space, FRC,pulmonary blood flow, and lung inhomogeneity) and that can also beapplied to a ventilated patient. The method and apparatus of the presentinvention can be used for other patient groups such as neonates andelderly patients, or other patient groups who cannot co-operate easilywith clinicians, such as the obese (who cannot be put in a bodyplethysmography).

The invention is based upon the inspired sinewave technique, whichdiffers from the above-mentioned techniques of rebreathing andwash-in/wash-out in that concentration of an inspired gas is forced tofollow a sinewave pattern. The expired concentration of the same gaswill also follow a sinewave pattern.

The use of the inspired sinewave technique has been previouslyinvestigated, but resulted in significant errors leading to incorrectresults and a technique that could not be used clinically. Inparticular, because of hardware limitations and rudimentary analyticaltechniques, the dead space recovered was over-estimated, which thenresulted in an under-estimation of the FRC and pulmonary blood flow:estimated blood flow was 3 L/min compared to the expected 5.6 L/min fora male and 4.9 L/min for a female (Clifton et al., 2013 (tworeferences)). Steps to address robustness and outliers were also notdescribed, which further added to the inaccuracy and low repeatabilityof the estimation of the FRC and pulmonary blood flow. Table 1 belowshows the over-estimation of dead space using this previous method, inthree different setups of a mechanical bench lung with known dead space.

The present inventors have determined that these failings were based onnot taking into account the non-uniform variation of inspiredconcentrations in both the determination of dead space and thedetermination of functional residual capacity and pulmonary blood flow.Accordingly, it was not possible to use the technique to provide ameasurement of lung inhomogeneity. The present invention focuses oneliminating such inaccuracy by the techniques described herein, thusproviding an apparatus and method to implement the inspired sinewavetechnique in a clinical setting (such as a bedside setting or in anintensive care unit) or on ventilated patients. The present inventionprovides a method that can be used to accurately measure cardiopulmonaryparameters and provide a measurement of lung inhomogeneity.

Thus, according to a first aspect of the invention there is provided amethod for measuring anatomical dead space V_(D) in a lung, the methodcomprising:

-   -   (a) providing, in a supply of inspired gas, at least one        indicator gas for inhalation by a patient during a test, the        concentration of the indicator gas being controlled such as to        follow a sinewave pattern over successive breaths;    -   (b) measuring, over successive breaths, the flow rate and        concentration of the indicator gas during both inspiration and        exhalation of the patient;    -   (c) fitting sinewave envelopes to the measured concentration        values of the indicator gas over the successive breaths and,        from the fitted sinewave envelopes, determining the inspired        concentration F_(I), the mixed expired concentration F_(Ē), and        the end expired concentration F_(E) in respect of the indicator        gas for each breath; and    -   (d) calculating the anatomical dead space V_(D) for each of a        plurality of inspirations, by:        -   (i) calculating the tidal volume V_(T) for the given            inspiration by integrating over time, from the start of that            inspiration, the flow rate {dot over (V)}_(T)(t) of the            inspired gas for that inspiration;        -   (ii) calculating the volume of inspired indicator gas in the            given inspiration by integrating over time, from the start            of that inspiration, the product of the inspired            concentration F_(I) and the flow rate {dot over (V)}_(T)(t)            of inspired gas for that inspiration; and            -   (iii) calculating the dead space V_(D) for the given                inspiration, based on:                -   the tidal volume V_(T) for that inspiration;                -   the inspired concentration F_(I) of indicator gas                    for that inspiration;                -   the mixed expired concentration F_(Ē) of indicator                    gas for that inspiration; and                -   the alveolar gas concentration F_(A) for that                    inspiration, which is taken as the expired                    concentration F_(E) of indicator gas at the end of                    that expiration;                -   the calculating involving a conservation-of-mass                    principle during expiration, between the amount of                    indicator gas expired out and the sum of the amount                    of indicator gas remaining in the deadspace and the                    amount of indicator gas expired from the part of the                    lung where gas exchange has taken place, whereby,                    having determined the inspired concentration F_(I),                    the flow rate {dot over (V)}_(T)(t), the tidal                    volume V_(T), the mixed expired concentration F_(Ē),                    and the alveolar gas concentration F_(A), a mass                    balance equation is solved to give an estimation of                    the dead space V_(D) for each breath.

An advantage of this method over methods based on the Bohr methoddescribed above is that the Bohr method assumes that inspiredconcentration of the inert gas is uniform and constant. The presentinventors have found that the concentration of the inspired inert gas isnon-uniform and thus that estimation methods based on assuming a uniformconcentration will lead to significant error. The method of the presentinvention accommodates non-uniform concentration and thus provides anaccurate measurement of anatomical dead space within a lung. By way ofexample, Table 1 below shows that the estimation of dead space by anembodiment of the present invention out-performs (i.e. is more accuratethan) the estimation by the previous method (Clifton et al., 2013 (tworeferences)), in three setups of a laboratory mechanical bench lung withknown dead space.

This accurate measurement of anatomical dead space permits the accuratemeasurement of other lung parameters, such as functional residualcapacity, pulmonary blood flow and lung inhomogeneity as will bediscussed further below.

Preferably, in providing the at least one indicator gas for inhalation,the concentration of the indicator gas is controlled such as to follow asinewave pattern over successive breaths by:

-   -   providing flow control means for injecting the indicator gas        into the supply of inspired gas;    -   processing the measured flow rate and concentration of the        inspired indicator gas over each breath so as to determine, from        breath to breath, an injection rate for the inspired indicator        gas that will cause it to follow the sinewave pattern, and    -   providing feedback control to the flow control means, to cause        it to inject the indicator gas at the determined injection rate.

In some embodiments, part of the supply of inspired gas is taken fromambient air. In other embodiments, part of the supply of inspired gas isprovided by a ventilator.

Preferably the tidal volume V_(T) for each of the plurality ofinspirations is calculated using ∫_(t) _(insp) ^(t){dot over(V)}_(T)(t)×dt, where t_(insp) is the time at the start of inspirationand {dot over (V)}_(T)(t) is the inspired flow rate.

Preferably the dead space V_(D) for each of the plurality ofinspirations is calculated using an algorithm to solvef(V_(D))−F_(A)×V_(D)=(F_(Ē)−F_(A))×V_(T), where F_(A) is the alveolargas concentration, F_(Ē) is the mixed expired concentration and V_(T) isthe tidal volume.

Preferably the method further comprises applying an estimation method tothe calculated anatomical dead space values for the plurality ofinspirations, in order to remove outliers and obtain a final dead spacevalue {circumflex over (V)}_(D,final).

Preferably the estimation method is a robust estimation method, such asan M-estimator proposed by (Huber and Ronchetti, 2009):

${\hat{V}}_{D,{final}} = {\underset{\theta}{\arg\;\min}\left( {\sum\limits_{n = 1}^{n\_{total}}{\rho\left( {V_{D,n},\theta} \right)}} \right)}$in which θ is the parameter to estimate the final dead space value,V_(D,n) is the dead space value estimated for an n-th breath,ρ(V_(D,n),θ) is the Huber loss function:

${\rho\left( {V_{D,n},\theta} \right)} = \left\{ {\begin{matrix}{\frac{1}{2}\left( {V_{D,n} - \theta} \right)^{2}} & {{{for}\mspace{14mu}{{V_{D,n} - \theta}}} < k} \\{{k{{V_{D,n} - \theta}}} - {\frac{1}{2}k^{2}}} & {{{for}\mspace{14mu}{{V_{D,n} - \theta}}} \geq k}\end{matrix},} \right.$and k is a constant chosen based on the quality of the data. It shouldbe noted that the invention is not limited to this particularM-estimator; more sophisticated robust methods can also be used toremove outliers and improve the estimation of the final value of deadspace.

Preferably the robust estimation method provides a 95% confidenceinterval.

The method of the present invention may also include measuring one ormore of functional residual capacity, pulmonary blood flow and lunginhomogeneity.

One or both of the alveolar volume V_(A) and the pulmonary blood flow{dot over (Q)}_(P) may be estimated as slopes of a virtual 3D surfaceV_(A)×x+{dot over (Q)}_(P)×y=z, wherex _(n) =F _(A,n) −F _(A,n−1)y _(n)=λ×(F _(A,n) −F _(A))×Δt _(n);z _(n) =V _(D)×(F _(Ī,n) −F _(A,n−1))+V _(T,n)×(F _(A,n) −F _(Ī,n))in which V_(D) is the dead space volume, V_(T,n) is the tidal volume ofan n-th breath, λ is the solubility of the indicator gas, Δt_(n) is therespiration time of the n-th breath, F_(A,n) is the alveolarconcentration of the n-th breath, F_(v) is the concentration of themixed venous sinewave, and F _(IA,n) is the mixed inspired concentrationof the indicator gas as ‘seen’ by the alveolar compartment.

An advantage of this 3D surface approach is that it allows a robustestimation method (such as bisquare) to be used to remove outliers andto provide a confidence interval (e.g. a 95% confidence interval).

Thus, the method may further comprise steps such as maximum likelihoodtechniques to remove outliers from the estimated values of the alveolarvolume V_(A) and/or pulmonary blood flow {dot over (Q)}_(P), so as togive robust estimations of the alveolar volume V_(A) and/or pulmonaryblood flow {dot over (Q)}_(P), and corresponding confidence intervals(e.g. 95% confidence intervals).

The method may further comprise calculating the functional residualcapacity as the sum of the alveolar volume V_(A) and the dead spaceV_(D).

Preferably the data used for the calculation of the alveolar volumeV_(A) and/or the pulmonary blood flow {dot over (Q)}_(P) are obtainedusing a sinewave period in the range of 0.5 minutes to 5minutes—particularly preferably using a sinewave period of approximately3 minutes.

To obtain a measurement of lung inhomogeneity, the method may furthercomprise:

-   -   varying the period of the sinewave during the course of the        test;    -   determining, at different sinewave periods, values of one or        more of the dead space V_(D), alveolar volume V_(A), functional        residual capacity, and pulmonary blood flow {dot over (Q)}_(P);        and    -   providing a measurement of lung inhomogeneity based on the        variation in the determined values with sinewave period.

For example, the period of the sinewave may be varied across the rangeof 0.5 minutes to 5 minutes. Of these, periods in the range of 2 minutesto 4 minutes may advantageously be used to determine inhomogeneity inrespect of one or more of the alveolar volume V_(A), functional residualcapacity, and pulmonary blood flow {dot over (Q)}_(P).

The method may further comprise evaluating one or more of the followingindices I₁, I₂, I₃ and I₄, wherein:

${I_{1} = \frac{{V_{A}\left( {4\mspace{14mu}{mins}} \right)} - {V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}},{I_{2} = \frac{V_{A,{predict}}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}},{I_{3} = \frac{V_{A,{plethysmograph}}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}},{and}$${I_{4} = \frac{{{\overset{.}{Q}}_{P}\left( {2\mspace{14mu}{mins}} \right)} - {{\overset{.}{Q}}_{P}\left( {4\mspace{14mu}{mins}} \right)}}{{\overset{.}{Q}}_{P}\left( {4\mspace{14mu}{mins}} \right)}};$in which V_(A)(0.5 mins) and V_(A)(4 mins) are the lung volume estimatedat sinewave periods of 0.5 minutes and 4 minutes respectively; {dot over(Q)}_(P)(2 mins) and {dot over (Q)}_(P)(4 mins) are the pulmonary bloodflow estimated at sinewave periods of 2 minutes and 4 minutesrespectively, V_(A,plethysmograph) is the lung volume measured by bodyplethysmography, and V_(A,predict) is the predicted lung volumecalculated from the height and weight of the subject.

The indicator gas may be nitrogen, nitrous oxide or oxygen. Additionallyor alternatively, other inert gases such as argon may be used as theindicator gas.

If desired, in practical implementations, at least one of the fitting ofthe sinewave envelopes to the measured concentration values, and thecalculating, may be performed after the test has been carried outoptionally without the patient being present. Alternatively the fittingof the sinewave envelopes to the measured concentration values, and thecalculating, may be performed in an ongoing manner, at periodicintervals, with the patient present, in order to provide continuousmonitoring of the patient.

According to a second aspect of the invention there is provided a methodfor measuring anatomical dead space in a lung, the method comprising:

-   -   (a) providing, in a supply of inspired gas, at least one        indicator gas for inhalation by a patient during a test, the        concentration of the indicator gas being controlled such as to        follow a sinewave pattern over successive breaths;    -   (b) measuring, over successive breaths, the flow rate and        concentration of the indicator gas during both inspiration and        exhalation of the patient;    -   (c) fitting sinewave envelopes to the measured concentration        values of the indicator gas over the successive breaths and,        from the fitted sinewave envelopes, determining the inspired        concentration, the mixed expired concentration, and the end        expired concentration in respect of the indicator gas for each        breath; and    -   (d) calculating the anatomical dead space for each of a        plurality of inspirations based on a conservation-of-mass        principle.

The above-described “preferable” or optional features in relation to thefirst aspect of the invention are also applicable to the second aspectof the invention.

According to a third aspect of the invention there is provided testapparatus configured for carrying out the above-described methods of thefirst and second aspects of the invention.

Preferably the apparatus comprises one or more mass flow controllers asmeans for injecting the indicator gas(es) into the supply of inspiredgas.

Preferably the apparatus comprises a diffusing injector for injectingthe indicator gas(es) into the supply of inspired gas.

Preferably the apparatus comprises a real-time flow rate sensor as meansfor measuring the flow rate of the inspired and expired gases.

Preferably the apparatus comprises a mainstream gas analyser as meansfor measuring the concentration of the indicator gas(es) duringinspiration and exhalation.

Preferably the apparatus comprises a processor provided with instructioncode which, when executed, causes the processor to control the mixing ofthe indicator gas with the other inspired gas(es) according to thebreathing flow of the patient, so that the concentration of theindicator gas follows a sinewave pattern over successive breaths.

Preferably the instruction code, when executed, provides a user withcontrol means operable to adjust one or more of the magnitude, phase,means and period of the indicator gas(es) delivered to the patient.

Particularly preferably the control means are operable to make theadjustment(s) in real time.

Preferably the apparatus comprises a processor provided with instructioncode which, when executed, causes the processor to record the measuredflow rate and concentration of the indicator gas(es) during inspirationand exhalation of the patient. This processor may be the same as theprocessor mentioned above, or may be a different processor.

Preferably the apparatus further comprises display means configured todisplay the flow and concentration of the indicator gas(es) in realtime.

The instruction code, when executed, may further cause the processor tocalculate one or more of the anatomical dead space V_(D), the alveolarvolume V_(A), the pulmonary blood flow {dot over (Q)}_(P) and thefunctional residual capacity, optionally together with 95% confidenceintervals, and these results may be displayed on the display means.

The test apparatus may further comprise one or more indicator gassupplies, e.g. in the form of gas canisters.

The test apparatus may be in the form of a portable unit. For example,it may be wheel-mounted in trolley-like form, for use for example in aclinical environment such as by a patient's bedside or in an operatingtheatre or intensive care unit.

Alternatively the test apparatus may be incorporated in a ventilator.

Thus, a further aspect of the invention provides a ventilator comprisingtest apparatus in accordance with the second aspect of the invention.

According to a yet further aspect of the invention there is provided acomputer program or set of instruction code which, when executed, causesa processor to implement a method in accordance with the first aspect ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention will now be described, by way of exampleonly, and with reference to the drawings in which:

FIG. 1 shows a schematic diagram illustrating a setup for the inspiredsinewave test, according to an embodiment of the invention;

FIG. 2a is a schematic illustration of a graphical user interfaceaccording to an embodiment of the invention, showing (i) displays ofsignals in real time, (ii) control panels, and (iii) displays of testresults, and FIG. 2b depicts a pop-up screen within the graphical userinterface, allowing more detailed analysis of the test results;

FIG. 3 shows an example setup of an embodiment of the invention, forstandalone and mobile use in clinical environments (this representingonly one possible way in which the invention can be embodied; anotheroption, for example, is to incorporate the invention into a ventilatoras a module);

FIG. 4 shows an example of the concentration signal in an inspiredsinewave test;

FIG. 5 shows an example of the breathing patterns during an inspiredsinewave test, and how the portions of gases remaining in the dead spaceare determined, also accounting for variations in the inspiredconcentrations, according to an embodiment of the invention;

FIG. 6 shows how the dead space may be computed from tidal volume andthe volume of the indicator gas remaining in the dead space according toequation (15), details of which are described below in relation to anembodiment of the invention;

FIG. 7 details a computational algorithm that is used in an embodimentof the invention to solve equation (15);

FIG. 8 shows an example of dead space estimation for an inspiredsinewave test, with the dots representing values of dead space estimatedin individual breaths, and the horizontal line representing the meandead space, obtained after outliers are removed;

FIG. 9 shows a tidally ventilated “balloon on a straw” model of thelung;

FIG. 10 demonstrates the determination of FRC and pulmonary blood flowas the slopes of a 3D surface;

FIG. 11 shows a Bland Altman Plot comparing FRC measurements by BodyPlethysmography and FRC estimations by an Inspired Sinewave Deviceaccording to an embodiment of the present invention;

FIG. 12 shows a simulation study of frequency/period response of aninhomogeneous lung, with the solid lines showing the effective lungparameters as functions of forcing periods, and the dashed lines showingthe values that would be the lung parameters if the lung was perfectlyhomogeneous;

FIG. 13a shows the period dependency of recovered FRC in a group ofhealthy volunteers, and FIG. 13b shows the corresponding perioddependency of pulmonary blood flow ({dot over (Q)}_(P)), obtained usingan embodiment of the present invention;

FIG. 14 shows the inhomogeneity difference in groups of healthy youngsubjects (solid line), and asymptomatic asthma subjects (dashed line);and

FIG. 15 shows inspired sinewave test results of three adult ventilatedpatients in operating theatres, obtained using an embodiment of thepresent invention, showing the period response of lung volume andpulmonary blood flow and also the change of lung volume versus positiveend expired pressure setting (with details of the three patients beinggiven in the table at the bottom of the figure).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Overview of the Inspired Sinewave Device

With reference to the figures, FIG. 1 provides an overview of thefunctional arrangement of an inspired sinewave device 10 according to anembodiment of the invention.

As illustrated, the inspired sinewave device 10 comprises a breathingtube 11, a mainstream gas analyser 12, a flow sensor 13, a dataacquisition unit 14, a processing unit 15 configured to implementanalysing algorithms, a N₂O mass flow controller 16, an O₂ mass flowcontroller 17, a mixing nozzle 18, and a controller 19.

In use, the patient breaths through the breathing tube 11 either by amouthpiece or a face mask. The other end of breathing tube 11 is eitherconnected to air (for spontaneous breathing patients) or to a ventilator(for ventilated patients). On this breathing tube 11, the mainstream gasanalyser 12 is mounted to measure the concentration of N₂O, andpotentially of O₂ and CO₂ too. For example, infrared sensors can be usedto measure N₂O and CO₂ concentrations. For measuring O₂ concentration, afuel cell sensor can be used. Also on this breathing tube 11, flowsensor 13 is attached to measure the flow rate as accurately as possiblein real time. For example, an ultrasound flow sensor can be used tomeasure the flow rate. The signals from the gas analyser 12 and flowsensor 13 are acquired and processed by the data acquisition unit 14,before feeding into the processing unit 15 which implements analysisalgorithms on the acquired signals. The analysis algorithms perform thenecessary calculation steps to give robust and accurate estimations ofthe cardiopulmonary parameters. Details of these steps will be describedlater.

A key aspect of embodiments of the invention is to have theconcentrations of the inspired indicator gases follow sinusoidalpatterns, and this is achieved using feedback control by the gas mixingapparatus (16, 17, 18, 19) also shown in FIG. 1. The gas mixingapparatus includes high speed N₂O and O₂ mass flow controllers 16 and 17respectively, to inject N₂O and O₂ into the breathing tube 11. Duringinspirations, the gases in the breathing tube 11 is a mixture of inletgas (either air or from a ventilator), injected N₂O and injected O₂, tocreate the desired N₂O and O₂ concentrations.

At the start of each inspiration, the desired concentrations aredetermined as the values of the inspired sinusoidal waveforms at thatpoint in time. By measuring the real time flow rate using the flowsensor 13, the controller 19 computes the desired injection ratesaccording to the instantaneous breathing rate of the patient and thedesired concentrations. The controller 19 then sends commands to massflow controllers 16 and 17 to inject the required amount of N₂O and O₂into the breathing tube 11 through the mixing nozzle 18. The mixingnozzle 18 diffuses the injected N₂O and O₂ evenly in the breathing tube18 to create the mixture of gases with the desired concentrations, whichis then inhaled by the patients. The formulae and algorithm implementedby controller 19 to determine the desired injection rates from the flowrate and inspired sinusoidal waveforms will be described later. Eventhough a system of two mass flow controllers 16, 17 for N₂O and O₂ isdemonstrated here, it is easy to extend this system to include more massflow controllers if more sinewaves of gases are required. For example, amass flow controller for argon could be added to generate an inspiredsinewave of argon.

Another aspect of embodiments of the invention is to integrate flow andconcentration signals to obtain the amounts of gases inspired/expiredduring the test. Signal synchronisation has been a problem for massspectrometers and side-stream gas analysers. As samples of gases need tobe sucked out of the breathing tube, side-stream gas analysers have along and varying time delay that can cause errors in integration.Methods have been developed to address this signal synchronisationproblem, such as one used by the LUFU system (Draeger Medical; LObeck,Germany) that synchronises flow and FiO₂ (fraction of inspired oxygen)signals while adjusting for gas viscosity (Weismann et al., 2006). Forthe present embodiments, a mainstream gas analyser 12 is used andtherefore eliminates the problem of long time delay between signals. Themainstream gas analyser 12 can be of any technology available formainstream sensing such as infrared for CO₂ and N₂O, fuel cell for O₂,and optical laser for O₂, CO₂ and N₂O. As shown in FIG. 1, the main gasanalyser 12 is mounted directly onto the breathing tube 11, and inseries with the flow sensor 13, allowing straightforward integration.With this setup, the time delay has been determined experimentally asbeing less than 10 ms, and can be corrected straightforwardly in thesoftware.

The device also includes a controller 19 (that may be, for example,microprocessor-controlled or computer-controlled) to control the massflow controllers 16, 17, record sensor data, and analyse test results inreal time. As part of embodiments of the invention, the computercontroller 19 used by the device has a graphical user interface designedspecifically to facilitate the administering of the inspired sinewavetechnique in a clinical environment, such as by the patient's bedside orin an operating theatre or intensive care unit.

Towards this objective, as shown in FIG. 2a , the graphical userinterface includes table 21 for entering patient information (e.g. name,age, height, weight, etc.), table 22 for entering sinewave parameters(e.g. mean, amplitude and phase of O₂ sinewave; and mean, amplitude andphase of N₂O sinewave), table 23 for displaying test results, controlpanel 24 for controlling the sinewave test, display 25 for displayingreal time flow and volume signals, and display 26 for displaying realtime concentrations of gases. Table 23 includes both values and 95%confidence intervals of estimated dead space, FRC, pulmonary blood flow,and lung inhomogeneity. Control panel 24 includes START, STOP andCALIBARATION (“CALIB”) buttons, and also dials for manual control ofinspired gas concentrations. Once a sinewave test completes, a pop-upscreen 27 (FIG. 2b ) with cursors also allows more detailed analysis ofresults within the graphical user interface. Table 28 and waveforms 29respectively show the more detailed results and sinewave data withinpop-up screen 27.

The software and processing algorithms used in the present embodimentsmay be provided as a computer program or set of instruction code capableof being executed by a computer processor. The computer processor may bethat of a conventional (sufficiently high performance) computer, or maybe an application-specific processor. The computer processor mayprovided in a computing device separate from, but in communication with,the test apparatus; or may be incorporated in the test apparatus itself.

The computer program or set of instruction code may be supplied on acomputer-readable medium or data carrier such as a CD-ROM, DVD or solidstate memory device. Alternatively, it may be downloadable as a digitalsignal from a connected computer, or over a local area network or a widearea network such as the Internet. As a further alternative, thecomputer program or set of instruction code may be hard-coded in thecomputer processor (or memory associated therewith) that is to executeit.

FIG. 3 shows a prototype hardware setup of an embodiment of theinvention, for ease of use by the patient's bedside, e.g. in anoperating theatre or intensive care unit. The whole system 30 is mountedon wheels and brakes 31 for mobile use, i.e. in the form of a trolley.Gas cylinders 32 supplying the required gases are also mounted on thetrolley. An articulated arm 33 is attached to hold the breathing tube 11(of FIG. 1), which also includes the gas mixing apparatus, flow sensor13, and gas analyser 12. A computer and display 34, preferably touchscreen type, is used to control the test, and analyse and displayresults. The pressure and flow control hardware 35 for the gas mixingapparatus is kept on shelves mounted on the trolley. This only shows onepossible setup of an embodiment of the invention, and does not limit theinvention in any way. Those skilled in the art will be able to suggestmany alternative setups of implementation without departing from thescope of the appended claims. For example, another possible setup is asmaller unit which can be incorporated into a ventilator as a module.

FIG. 4 demonstrates an example of the concentration generated andmeasured in an inspired sinewave test, and also how the sinewaves aredetermined. Line 41 shows the concentration signal measured by the gasanalyzer 12 (of FIG. 1). On a closer look, this signal contains twocomponents (sinewave envelopes): inspired concentration corresponding tothe inspiration phase, and expired concentration corresponding to theexpiration phase. By calculating the mixed inspired and mixed expiredconcentrations for each breath, a series of inspired and expiredconcentration points are generated as shown respectively by □ and xpoints on the plot. By fitting these points on two sinewaves, theinspired sinewave 42 and expired sinewave 43 are obtained. Thesesinewaves are the basis to determine cardiopulmonary parameters in aninspired sinewave test.

Description of the Apparatus and Method to Mix Concentrations

At the core of the inspired sinewave technique, the inspiredconcentrations of the indicator gases need to follow sinewave patterns,which are defined by the following equations:

-   -   For O₂:

$\begin{matrix}{{F_{O_{2}}(t)} = {{\Delta\; F_{O_{2}} \times {\sin\left( {{\frac{2\pi}{T_{O_{2}}}t} + \varphi_{O_{2}}} \right)}} + {\overset{\_}{F}}_{O_{2}}}} & (1)\end{matrix}$

-   -   For N₂O:

$\begin{matrix}{{F_{N_{2}O}(t)} = {{\Delta\; F_{N_{2}O} \times {\sin\left( {{\frac{2\pi}{T_{N_{2}O}}t} + \varphi_{N_{2}O}} \right)}} + {\overset{\_}{F}}_{N_{2}O}}} & (2)\end{matrix}$in which ΔF_(O) ₂ and ΔF_(N) ₂ _(O) are the magnitudes, T_(O) ₂ andT_(N) ₂ _(O) are the periods, φ_(O) ₂ and φ_(N) ₂ _(O) are the phaseshifts, and F _(O) ₂ and F _(N) ₂ _(O) are the means of O₂ and N₂Osinewaves respectively.

During the inspired sinewave test, the desired inspired concentrationsof an n-th breath are then determined as the values of sinewaves (1),(2) at the starting time of the n-th inspiration:F _(O) ₂ _(,desired,n) =F _(O) ₂ (t _(insp,n) ^(start))  (3)F _(N) ₂ _(O,desired,n) =F _(N) ₂ _(O)(t _(insp,n) ^(start))  (4)

The desired concentrations of the inspired gases are then obtained bythe gas mixing apparatus described earlier (16, 17, 18, 19 of FIG. 1)and an algorithm to set the desired N₂O and O₂ as follows.

Consider the conservation of mass for the breathing tube 11:

-   -   For all gases        {dot over (V)} _(intake) +{dot over (V)} _(O2) +{dot over (V)}        _(N2O) ={dot over (V)} _(inspired)  (5)        where {dot over (V)}_(intake) is the rate of total volume of        gases taken-in by the tube 11, which can come from air (for        spontaneous breathing) or ventilators (for ventilated patients);        {dot over (V)}_(O2) is rate of O₂ injected to the tube 11; {dot        over (V)}_(N2O) is the rate of N₂O injected to the tube 11; {dot        over (V)}_(inspired) is the rate of gases inspired by the        subject.    -   For O₂:        F _(O2,intake) ×{dot over (V)} _(intake)+100%×{dot over (V)}        _(O2) =F _(O2,desired) ×{dot over (V)} _(inspired)  (6)        where F_(O2,intake) and F_(O2,desired) are the O₂ concentrations        of the intake and inspired gases respectively.    -   For N₂O:        F _(N2O,intake) ×{dot over (V)} _(intake)+100%×{dot over (V)}        _(N2O) =F _(N2O,desired) ×V _(inspired)  (7)        where F_(N2O,intake) and F_(N2O,desired) are the N₂O        concentrations of the intake and inspired gases respectively.

With {dot over (V)}_(inspired) measured by the flow sensor 13 in realtime (and provided via the feedback control loop indicated in FIG. 1),and F_(O2,intake) and F_(N2O,intake) known, the required {dot over(V)}_(O2) and V_(N2O) to be injected into the breathing tube 11 can bedetermined by solving equations (5), (6) and (7).

The invention is not limited to only two gases, O₂ and N₂O. More gases(such as argon) can be easily added and the same principle can beapplied to obtain the desired concentrations. Moreover, for flexibility,an additional gas port can also be installed on the breathing tube torelease some gases. This flexibility is useful when connecting thedevice to ventilators and an exact tidal volume is desirable.

The method described by equations (5), (6), (7) does not consider thedynamics of mass flow controllers, hardware limitations, and time delay.Even with the best effort, the desired concentrations cannot be obtainedwith absolutely no error. A possible solution is to incorporate anadditional feedback control loop (in addition to the internal controlloops of the mass flow controllers and the flow feedback loop). However,this could be costly and may not eliminate error entirely. A moreflexible approach is to consider and compensate for the error in theestimations of cardiopulmonary parameters. Such a compensation algorithmfor the estimation of dead space is described in the following section.

Estimation of Dead Space (V_(D))

Airway dead space is an important parameter regarding the efficiency ofventilation and its relation to pulmonary perfusion (Tang et al., 2006),with applications in respiratory physiology, clinical anaesthesia, andcritical care medicine. In the present embodiments, a method to estimatedead space, based on the Bohr method and taking into account thenon-uniform inspired concentration caused by noise and error in mixinggases method, is described as follows.

The Bohr method assumes that the inspired concentration of the indicatorgas is uniform and constant so thatF _(I)(t)=F _(IA)(t)=F _(I)  (8)in which F_(I)(t) is the inspired concentration of a tracer gas, andF_(IA)(t) is the inspired concentration of the same tracer gas “seen” bythe alveoli. From the mass balance equation, the general Bohr equationcan be derived as:

$\begin{matrix}{V_{D} = {V_{T}\frac{F_{A} - F_{\overset{\_}{E}}}{F_{A} - F_{I}}}} & (9)\end{matrix}$

in which V_(D) is the dead space, V_(T) is the tidal volume, and F_(I),F_(A) and F_(Ē) are the inspired, alveolar, and mixed expiredconcentrations respectively. For the special case of CO₂, there is noCO₂ in the dead space at the end of an inspiration, i.e. F_(I,CO2)=0.The Bohr dead space becomes (Tang et al., 2006; West, 2008):

$\begin{matrix}{V_{D,{C\; O\; 2}} = {V_{T}\frac{F_{A,{C\; O\; 2}} - F_{\overset{\_}{E},{C\; O\; 2}}}{F_{A,{C\; O\; 2}}}}} & (10)\end{matrix}$

When the concentration of the inspired indicator gas is non-uniform,such as shown in FIG. 3, the dead space estimation method such as Bohrequations (9, 10), or U.S. Pat. No. 6,599,252 B2 (Starr, 2003) cannot beapplied. In embodiments of the present invention, we propose a modifiedBohr method as follows.

The gases that pass the lips consist of two parts. One part travels downto the alveoli level and is “seen” by the alveolar compartment. Theother part never reaches the alveolar compartment and remains in thedead space. FIG. 5 demonstrates how the two parts are defined duringinspirations and expirations. In FIG. 5, t_(ins,n) and t_(exp,n) are theinspiration and expiration times respectively of a breath circle. Fortwo subsequent breaths, the part of expired gas that remains in the deadspace at the end of expiration will be re-inhaled by the nextinspiration, and is defined as t_(eds,n−1) and t_(ids,n) for inspirationand expiration respectively. The total inspired volume and inspiredindicator volume that pass the lips during an inspiration are thencalculated respectively from the flow and concentration signals as:total inspiredgas volume=∫_(t) _(insp) ^(t) {dot over (V)}_(T)(t)×dt  (11)andinspired indicator gas volume=∫_(t) _(insp) ^(t) F _(I)(t)×{dot over(V)} _(T)(t)×dt  (12)where t_(insp) is the time at the start of inspiration, and {dot over(V)}_(T)(t) is the inspired flow rate. An example of these two functionsis demonstrated in FIG. 6.

The indicator gas remaining in the dead space at the end of an n-thinspiration is:indicator gas remained in the dead space_(n-th)=∫_(t) _(VT-VD) ^(t)^(VT) F _(I)(t)×{dot over (V)} _(T)(t)×dt  (13)where t_(VT-VD) is the time after which any gas that passes the lipsonly fills the dead space, and t_(VT) is the time at the end of theinspiration. With V_(D) unknown, equation (13) can be interpreted as afunction of dead space where V_(D) can take a value between 0 and V_(T):f(V _(D))=∫_(t) _(VT-VD) ^(t) ^(VT) F _(I)(t)×{dot over (V)}_(T)(t)×dt  (14)

As the indicator gas remaining in the dead space at the end of aninspiration will go out in the next expiration, the mass balanceequation becomes:indicatorgas_(out)=indicatorgas_(deadspace) +F _(A)×(V _(T) −V _(D))

F _(Ē) ×V _(T) =f(V _(D))+F _(A)×(V _(T) −V _(D))

f(V _(D))−F _(A) ×V _(D)=(F _(Ē) −F _(A))×V _(T)  (15)

By solving equation (15), the dead space can be calculated for eachbreath. FIG. 7 details the computational algorithm that is used inembodiments of the invention to solve equation (15).

Once the dead space values for all the breaths are determined, a robustestimation method such as an M-estimator proposed by (Huber andRonchetti, 2009) is used to determine the final dead space value and the95% confidence interval:

$\begin{matrix}{{\hat{V}}_{D,{final}} = {\underset{\theta}{\arg\;\min}\left( {\sum\limits_{n = 1}^{n\_{total}}{\rho\left( {V_{D,n},\theta} \right)}} \right)}} & (16)\end{matrix}$in which θ is the parameter to estimate final dead space value, V_(D,n)is the dead space value estimated for the n-th breath, and ρ(V_(D,n),θ)is the Huber loss function:

$\begin{matrix}{{\rho\left( {V_{D,n},\theta} \right)} = \left\{ \begin{matrix}{\frac{1}{2}\left( {V_{D,n} - \theta} \right)^{2}} & {{{for}\mspace{14mu}{{V_{D,n} - \theta}}} < k} \\{{k{{V_{D,n} - \theta}}} - {\frac{1}{2}k^{2}}} & {{{for}\mspace{14mu}{{V_{D,n} - \theta}}} \geq k}\end{matrix} \right.} & (17)\end{matrix}$and k is a constant chosen based on the quality of the data. It shouldbe noted that the invention is not limited to this particularM-estimator; more sophisticated robust methods can also be used toremove outliers and improve the estimation of the final value of deadspace.

FIG. 8 demonstrates an example of how the dead space is determined over150 breaths by the device after removing outliers. The dots representvalues of dead space estimated in individual breaths. The horizontalline is the mean dead space, obtained after outliers are removed.

Table 1 below sets out the results of a comparison study between theprevious method (of Clifton et al., 2013 (two references)) and thepresent new method to estimate lung dead space, in three differentsetups of a laboratory mechanical bench lung with known dead space. Thisshows that the present new method produces much smaller error andstandard deviation values compared to the previous method.

TABLE 1 The results of a comparison study between the previous method(of Clifton et al., 2013 (two references)) and the present new method toestimate lung dead space, in three different setups of a laboratorymechanical bench lung with known dead space. Actual dead space set onthe mechanical bench lung 118 ml 208 ml 258 ml Dead space estimated 228± 26 ml 327 ± 20 ml 393 ± 26 ml by previous method Dead space estimated110 ± 10 ml 206 ± 8 ml 260 ± 8 ml by new method Error of previous 110 ±26 ml 119 ± 20 ml 135 ± 26 ml method Error of new method 8 ± 10 ml −2 ±8 ml 2 ± 8 mlEstimating Functional Residual Capacity (FRC) and Pulmonary Blood Flow{dot over (Q)}_(P)

Embodiments of the invention also provide a method to determine thefunctional residual capacity and pulmonary blood flow simultaneously andbreath by breath. These two cardiopulmonary parameters are determinedbased on the tidal “balloon on a straw” lung model (Hahn and Farmery,2003) shown in FIG. 9. The lung is considered as a single serial deadspace connected to a single compartment lung. F_(I)(t) is the inspiredconcentration as a function of time t. F_(IA)(t) is the inspiredconcentration “seen” by the alveolar at time t. V_(A)(t) and F_(A)(t)are the volume and tracer concentration in the alveolae respectively,and F_(E)(t) is the expired concentration.

The dead space is defined as the portion of inspired gas that passes thelips but never gets to the alveolar compartment. During respiration, thelung extends from end-tidal volume V_(A) to V_(A)+V_(T) in which V_(T)is the tidal volume. Taking into account the non-uniform variation ofthe inspired concentrations, the mixed inspired concentration of atracer gas “seen” by the alveoli is calculated by:

$\begin{matrix}{F_{\overset{\_}{I\; A},n} = {\frac{1}{V_{T,n} - V_{D}}{\int_{t_{0,n}}^{t_{{V\; T},{n - {V\; D}}}}{{F_{I}(t)} \times {f(t)}\ {dt}}}}} & (18)\end{matrix}$in which t_(0,n) is the time at the start of inspiration of the n-thbreath, t_(VT,n-VD) is the time after which any gas that passes the lipsonly fills the dead space of the n-th breath.

From the conservation of mass and some mathematical manipulation, theequation governing the relationship of V_(A) and {dot over (Q)}_(P) is:V _(A)×(F _(A,n) −F _(A,n−1))+λ×{dot over (Q)} _(P)×(F _(A,n) −F_(v))×Δt _(n) =V _(D)×(F _(IA,n) −F _(A,n−1))+V _(T,n)×(F _(A,n) −F_(IA,n))  (19)in which V_(A) is the alveolar volume, V_(D) is the dead space volumeestimated by the aforementioned method, V_(T,n) is the tidal volume ofthe n-th breath, λ is the solubility of a tracer gas (0.47 for N₂O forexample), {dot over (Q)}_(P) is the pulmonary blood flow, Δt_(n) is therespiration of the n-th breath, F_(A,n) is the alveolar concentration ofthe n-th breath, F_(v) is the concentration of the mixed venoussinewave, and F _(IA,n) is the mixed inspired concentration of anindicator gas as ‘seen’ by the alveolar compartment.

At reasonable short periods (e.g. less than 5 minutes), theconcentration sinewave in the mixed venous blood is so diminished thatit can be assumed a constant, equal to the mean. The periods of theapplied inspired sinewaves are carefully chosen such that this conditionis satisfied. Equation (19) becomes:V _(A)×(F _(A,n) −F _(A,n−1))+λ×{dot over (Q)} _(P)×(F _(A,n) −F_(A))×Δt _(n) =V _(D)×(F _(IA,n) −F _(A,n−1))+V _(T,n)×(F _(A,n) −F_(IA,n))  (20)in which F _(A) is the concentration of the mixed venous sinewave.

As F_(A,n), F_(A,n−1), Δt_(n), F_(Ī,n), V_(T,n) can be measured orestimated from the sensors, for each breath n, a pointP_(n)(x_(n),y_(n),z_(n)) in 3-dimension (x,y,z) can be computed usingequation (20):x _(n) =F _(A,n) −F _(A,n−1)y _(n)=λ×(F _(A,n) −F _(A))×Δt _(n)z _(n) =V _(D)×(F _(Ī,n) −F _(A,n−1))+V _(T,n)×(F _(A,n) −F_(Ī,n))  (21)and a 3D surface V_(A)×x+{dot over (Q)}_(P)×y=z can be constructed fromthe points, in which V_(A) and {dot over (Q)}_(P) are the slopes of theconstructed surface. Alternative to the standard least square estimationmethod, maximum likelihood estimation techniques such as bisquare can beused to remove outliers to give the robust estimations of V_(A) and {dotover (Q)}_(P) and their corresponding 95% confidence intervals. FIG. 10demonstrates how alveolar volume and pulmonary blood flow can beestimated using equations (20, 21) in an inspired sinewave test.

Having determined V_(A) in this way, FRC can then be estimated throughthe relationship FRC=V_(D)+V_(A) with V_(D) being determined asdiscussed above.

FIG. 11 demonstrates the estimation of FRC by the methods described inthis work in comparison to the gold standard body plethysmography,showing a good agreement between two methods and a bias of 0.6 L. Thebias of 0.6 L is comparable to other respired gases techniques whencomparing with the body plethysmography. Past and ongoing clinicalresearch suggests that body plethysmography often overestimates FRC incomparative studies involving chest Computed Tomography (CT) and HeliumDilution. Possible reasons include presence of gas in abdominal cavitiesand a degree of dependency of panting frequency on mouth—alveolipressure equilibration. Helium Dilution often underestimates lung volumedue to effects of gas trapping, although both anomalies are thought tobe less pronounced in healthy subjects.

Due to lung inhomogeneity as shown in FIG. 12 and FIG. 13, V_(A)estimated at shorter sinewave periods underestimates actual volume. Onthe other hand, {dot over (Q)}_(P) estimated at longer sinewave periodsbecomes unreliable due to the fact that, at longer periods, thesinusoidal signal in the recirculating venous blood becomes sizeable andcannot now be neglected. The sinewave period of 3 minutes is chosenclinically to provide the most accurate and reliable estimations:FRC=V _(D) +V _(A)(3 mins)  (22){dot over (Q)} _(P) ={dot over (Q)} _(P)(3 mins)  (23)in which FRC is the functional residual capacity, V_(A)(3 mins) and {dotover (Q)}_(P)(3 mins) are the alveolar volume and pulmonary blood followestimated using a sinewave period of 3 mins.Measurement of Inhomogeneity

The clinical value measuring lung inhomgeneity is that traditional testsof lung function (peak flow, forced vital capacity in 1 second, forcedexpiratory volume (FEV1), etc.) are notoriously insensitive. Significantabnormalities in FEV1 are only evident when the diagnosis is wellestablished and disease moderately advanced and severe. It isestablished that ventilatory and V/Q inhomogeneity become abnormal inthe early, subclinical stages of many respiratory diseases such aschronic obstructive pulmonary disease (COPD) and cystic fibrosis. Thesechanges are detectable on hyperpolarized Xenon MRI scanning, but thereis currently no clinically reliable test for these subtle changes whichcan be simply deployed in the clinic or at the bedside.

A key advantage of using inspired sinewaves is the dependency of therecovered parameters on the chosen sinewave periods. This dependencyprovides insight and useful information about, and quantification of thedegree inhomogeneity of ventilation and ventilation:perfusion ratiothroughout the lung. However, no method has been described in the stateof the art to process the frequency/period dependency of the recoveredparameters, or to use this to provide a quantification of lunginhomogeneity. It is the purpose of an embodiment of the presentinvention to provide such a method, with details given as follows.

FIG. 12 shows a simulation study with a tidal inhomogeneous lung model,demonstrating that lung parameters recovered depends on the periods ofthe sinewaves applied, and that level of dependency reflects lunginhomogeneity.

FIGS. 13a and 13b display the mean response of a group of healthysubjects obtained by the methods of the present work, as describedabove, across a range of sinewave periods. FIG. 13a shows the sinewaveperiod dependency of recovered FRC, and FIG. 13b shows the correspondingperiod dependency of pulmonary blood flow {dot over (Q)}_(P) (althoughidentified simply as “Q_(P)” in the graph). With reference to FIG. 13b ,for robust and accurate estimation the method only uses values between 2mins and 4 mins for estimation of pulmonary blood flow. Pulmonary bloodflows below 2 mins and above 4 mins are affected by noise sensitivityand recirculation. Details of the steps used to obtain these data aredescribed above.

Index of ventilation-volume inhomogeneity is represented by the gradient(dashed line) of the period response on the FRC graph in FIG. 13a .Similarly, index of ventilation-perfusion inhomogeneity is representedby the gradient of the period response between 2 mins and 4 mins, on the{dot over (Q)}_(P) graph in FIG. 13 b.

There is a small degree of inhomogeneity even in healthy subjectscompared to the ideal lung, and the slopes of the response reflect thedegree of inhomogeneity. For sinewave periods smaller than 2 mins, thepulmonary blood flow estimated is sensitive to noise, whereas forsinewave periods larger than 4 mins, the pulmonary blood flow estimatedis inaccurate due to excessive recirculation of the venous signal. Theperiod range of interest for pulmonary blood flow is therefore between 2mins and 4 mins.

During an inspired sinewave test, a subject is tested at differentsinewave periods such as 0.5, 1, 2, 3, 4, 5 mins. The results can thenbe used to construct a period response of the subject. This periodresponse is then plotted against normalised maps of healthy and diseasedgroups such as the ones shown in FIG. 14, to derive a measurement ofinhomogeneity. In addition, to quantify the inhomogeneity, embodimentsof the present invention also define four indices as:

$\begin{matrix}{I_{1} = \frac{{V_{A}\left( {4\mspace{14mu}{mins}} \right)} - {V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}} & (24) \\{I_{2} = \frac{V_{A,{predict}}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}} & (25) \\{I_{3} = \frac{V_{A,{plethysmograph}}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}} & (26) \\{I_{4} = \frac{{{\overset{.}{Q}}_{P}\left( {2\mspace{14mu}{mins}} \right)} - {{\overset{.}{Q}}_{P}\left( {4\mspace{14mu}{mins}} \right)}}{{\overset{.}{Q}}_{P}\left( {4\mspace{14mu}{mins}} \right)}} & (27)\end{matrix}$in which V_(A)(0.5 mins), V_(A)(4 mins) are the lung volume estimated atsinewave periods of 0.5 minutes and 4 minutes respectively; {dot over(Q)}_(P)(2 mins), {dot over (Q)}_(P)(4 mins) are the pulmonary bloodflow estimated at sinewave periods of 2 minutes and 4 minutesrespectively, V_(A,plethysmograph) is the lung volume measured by bodyplethysmography if available, and V_(A,predict) is the predicted lungvolume calculated from the height and weight of the subject, for exampleby the formula (Quanjer et al., 1993):

$\begin{matrix}{V_{A,{predict}} = \left\lbrack \begin{matrix}{{{2.34 \times {height}} + {0.01 \times {age}} - 1.09 - V_{D}},} & {male} \\{{{2.24 \times {height}} + {0.01 \times {age}} - 1 - V_{D}},} & {{fe}{male}}\end{matrix} \right.} & (28)\end{matrix}$

I₁, I₂, I₃ reflect inhomogeneity in only ventilation-volume, whereas I₄reflects the inhomogeneity in both ventilation-volume andventilation-perfusion. The larger these indices, the higher the level ofinhomogeneity, and so these have diagnostic significance. For example,FIG. 14 demonstrates the inhomogeneity difference in groups of healthyyoung and asymptomatic asthma. For a healthy young group, I₁=0.09 andI₃=1.43. For an asymptomatic asthma group, I₁=0.38 and I₃=2.38.

FIG. 15 demonstrates the use of an embodiment of the present inventionin three adult ventilated patients in operating theatres. It shows theperiod response of lung volume and pulmonary blood flow and also thechange of lung volume versus positive end expired pressure setting.Details of the three patients used in these trials are given in thetable at the bottom of FIG. 15.

Summary

The present work provides inter alia the following:

-   1) Apparatus to mix inspired gas at the mouth of patients,    comprising:    -   one or more mass flow controllers;    -   an accurate real-time flow sensor;    -   a diffusing injector in the breathing tube; and    -   computer software and algorithm to control the mixing of the        gases according to the breathing flow of the patients.-   2) Apparatus to determine total amounts of inspired/expired gas at    the mouth of the patient, comprising:    -   an accurate real-time flow sensor;    -   a mainstream fast-response gas analyser; and    -   computer software and algorithm to line up signals, compensate        and integrate to determine the correct amount of gases.-   3) A computer control interface of the inspired sinewave device,    which includes:    -   displays of flow and concentrations of gases in real time;    -   control panels allowing real time adjustment of magnitudes,        phases, means, and periods of the sinewaves of the indicator        gases delivered to the patients; and    -   displays of inspired sinewave test results, calculated inspired        and expired sinewaves, and table of estimated dead space ±95%        confidence interval, estimated FRC ±95% confidence interval,        pulmonary blood flow ±95% confidence interval-   4) A method to robustly estimate dead space breath by breath for    non-uniform indicator gases.-   5) A method to estimate functional residual capacity and pulmonary    blood flow simultaneously, breath by breath.-   6) A method to investigate lung inhomogeneity from the inspired    sinewave tests at different periods, including (but not limited to)    four indices.

REFERENCES

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The invention claimed is:
 1. A method for adjusting appropriateventilator settings in a ventilated patient in need thereof based oninformation obtained by measuring anatomical dead space V_(D) in a lung,the method comprising: (a) providing, in a supply of inspired gas, atleast one indicator gas for inhalation by a patient during use, theconcentration of the indicator gas being controlled by a mass flowcontroller such as to follow a sinewave pattern over successive breaths,wherein the ventilated patient inhales the inspired gas, by a breathingtube, and further wherein the concentration of the indicator gas iscontrolled, by the mass flow controller, such as to follow a sinewavepattern over successive breaths by: (i) providing flow control means forinjecting the indicator gas into the supply of inspired gas via thebreathing tube; (ii) processing, by a processing unit, a measured flowrate and concentration of the inspired indicator gas over each breath soas to determine, by a gas mixing controller, from breath to breath, aninjection rate for the inspired indicator gas that will cause theinspired indicator gas to follow said sinewave pattern, and (iii)providing feedback control from the gas mixing controller to the flowcontrol means, to cause the flow control means to inject the indicatorgas at the determined injection rate, the feedback control based on datacomprising the measured flow rate, concentration of the inspiredindicator gas, the injection rate from the mass flow controller, thesupply of the inspired gas, and feedback from a flow sensor and a gasanalyzer each in communication with the breathing tube; (b) measuring,by the flow sensor and the gas analyzer, over successive breaths, theflow rate and concentration of the indicator gas during both inspirationand exhalation of the patient; (c) fitting sinewave envelopes to themeasured concentration values of the indicator gas over the successivebreaths and, from the fitted sinewave envelopes, determining, by thesystem controller, the inspired concentration F_(I), the mixed expiredconcentration F_(Ē), and the end expired concentration F_(E) withrespect to the indicator gas for each breath; and (d) calculating, bythe system controller, the anatomical dead space VD for each of aplurality of inspirations, by: (i) calculating the tidal volume V_(T)for the given inspiration by integrating over time, from the start ofthat inspiration, the flow rate {dot over (V)}_(T) (t) of the inspiredgas for that inspiration wherein the tidal volume V_(T) for each of theplurality of inspirations is calculated using ∫_(t) _(insp) ^(t){dotover (V)}_(T)(t)×dt, where t_(insp) is the time at the start ofinspiration and {dot over (V)}_(T) (t) is the inspired flow rate; (ii)calculating the volume of inspired indicator gas in the giveninspiration by integrating over time, from the start to the end of thatinspiration, the product of the inspired concentration F_(I) and theflow rate {dot over (V)}_(T)(t) of inspired gas taken from theconcentration and flow rate signals respectively, from the start to theend of that inspiration; and (iii) calculating the dead space V_(D) forthe given inspiration, based on: the tidal volume V_(T) for thatinspiration; the inspired concentration F_(I) of indicator gas takenfrom the concentration signal, from the start to the end of thatinspiration; the mixed expired concentration F_(Ē) of indicator gas forthat inspiration; and the alveolar gas concentration F_(A) for thatinspiration, which is taken as the expired concentration F_(E) ofindicator gas at the end of that expiration; the calculating involving aconservation-of-mass principle during expiration, between the amount ofindicator gas expired out and the sum of the amount of indicator gasremaining in the dead space and the amount of indicator gas expired fromthe part of the lung where gas exchange has taken place, whereby, havingdetermined the inspired concentration F_(I), the flow rate {dot over(V)}_(T)(t), the tidal volume V_(T), the mixed expired concentrationF_(Ê), and the alveolar gas concentration F_(A), a mass balance equationis solved to give an estimation of the dead space V_(D) for each breath,wherein said mass balance equation comprisesf(V_(D))−F_(A)×V_(D)=(F_(Ē)−F_(A))×V_(T); (e) varying a period of saidsinewave pattern of concentration of the indicator gas over successivebreaths during use by the patient; determining, at different sinewavepattern periods, values of one or more of the dead space V_(D), alveolarvolume V_(A), functional residual capacity, and pulmonary blood flow{dot over (Q)}_(P); providing, by the system controller, a measurementof lung inhomogeneity based on the variation in the determined valueswith said sinewave pattern period, and (f) adjusting ventilator settingsin the ventilated patient in need thereof, based on said measurement oflung inhomogeneity, ventilator settings comprising at least one of tidalvolume, positive end expiratory pressure, magnitude, phase, means andperiod of sinewaves of the indicator gases delivered to the patient. 2.The method of claim 1, further comprising applying an estimation methodto the calculated anatomical dead space values for the plurality ofinspirations, in order to remove outliers and obtain an average deadspace value.
 3. The method of claim 2, wherein the estimation methodprovides a 95% confidence interval.
 4. The method of claim 3, wherein anM-estimator is used to determine the average dead space value and the95% confidence interval, the M-estimator using:${\hat{V}}_{D,{final}} = {\underset{\theta}{\arg\;\min}\left( {\sum\limits_{n = 1}^{n\_{total}}{\rho\left( {V_{D,n},\theta} \right)}} \right)}$in which θ is the parameter to estimate the dead space value, V_(D,n) isthe dead space value estimated for an n-th breath, ρ(V_(D,n),θ) is aloss function${\rho\left( {V_{D,n},\theta} \right)} = \left\{ {\begin{matrix}{\frac{1}{2}\left( {V_{D,n} - \theta} \right)^{2}} & {{{for}\mspace{14mu}{{V_{D,n} - \theta}}} < k} \\{{k{{V_{D,n} - \theta}}} - {\frac{1}{2}k^{2}}} & {{{for}\mspace{14mu}{{V_{D,n} - \theta}}} \geq k}\end{matrix},} \right.$ and k is a constant chosen based on the qualityof the data.
 5. The method of claim 4, further comprising estimating oneor both of the alveolar volume V_(A) and the pulmonary blood flow {dotover (Q)}_(P) as slopes of a virtual 3D surface V_(A)×x+{dot over(Q)}_(P)×y=z, wherex _(n) =F _(A,n) −F _(A,n−1)y _(n)=λ×(F _(A,n) −F _(A))×Δt _(n)z _(n) =V _(D)×(F _(Ī,n) −F _(A,n−1))+V _(T,n)×(F _(A,n) −F _(Ī,n)); inwhich V_(D) is the dead space volume, V_(T,n) is the tidal volume of ann-th breath, λ is the solubility of the indicator gas, Δt_(n) is therespiration time of the n-th breath, F_(A,n) is the alveolarconcentration of the n-th breath, F_(v) is the concentration of themixed venous sinewave, and F _(IA,n) is the mixed inspired concentrationof the indicator gas as ‘seen’ by the alveolar compartment.
 6. Themethod of claim 5, further comprising removing outliers from theestimated values of the alveolar volume V_(A) and/or pulmonary bloodflow {dot over (Q)}_(P), so as to give robust estimations of thealveolar volume V_(A) and/or pulmonary blood flow {dot over (Q)}_(P),and corresponding confidence intervals.
 7. The method of claim 6,further comprising calculating the functional residual capacity as thesum of the alveolar volume V_(A) and the dead space.
 8. The method ofclaim 6, wherein the data used for the calculation of the alveolarvolume V_(A) and/or the pulmonary blood flow {dot over (Q)}_(P) areobtained using a sinewave period in the range of 0.5 minutes to 5minutes.
 9. The method of claim 8, wherein the data used for thecalculation of the alveolar volume V_(A) and the pulmonary blood flow{dot over (Q)}_(P) are obtained using a sinewave period of approximately3 minutes.
 10. The method of claim 9, wherein the period of the sinewaveis varied across the range of 0.5 minutes to 5 minutes.
 11. The methodof claim 10, wherein periods in the range of 2 minutes to 4 minutes areused to determine inhomogeneity in respect of one or more of thealveolar volume V_(A), functional residual capacity, and pulmonary bloodflow {dot over (Q)}_(P).
 12. The method of claim 11, further comprisingevaluating one or more of the following indices I₁, I₂, I₃ and I₄,wherein:${I_{1} = \frac{{V_{A}\left( {4\mspace{14mu}{mins}} \right)} - {V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}},{I_{2} = \frac{V_{A,{predict}}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}},{I_{3} = \frac{V_{A,{plethysmograph}}}{V_{A}\left( {0.5\mspace{14mu}{mins}} \right)}},{and}$${I_{4} = \frac{{{\overset{.}{Q}}_{P}\left( {2\mspace{14mu}{mins}} \right)} - {{\overset{.}{Q}}_{P}\left( {4\mspace{14mu}{mins}} \right)}}{{\overset{.}{Q}}_{P}\left( {4\mspace{14mu}{mins}} \right)}};$in which V_(A) (0.5 mins) and V_(A) (4 mins) are the lung volumeestimated at sinewave periods of 0.5 minutes and 4 minutes respectively;{dot over (Q)}_(P) (2 mins) and {dot over (Q)}_(P) (4 mins) are thepulmonary blood flow estimated at sinewave periods of 2 minutes and 4minutes respectively, V_(A,plethysmograph) is the lung volume measuredby body plethysmography, and V_(A,predict) is the predicted lung volumecalculated from the height and weight of the subject.
 13. The method ofclaim 12, wherein at least one of the fitting of the sinewave envelopesto the measured concentration values, and the calculating, is performedafter the test has been carried out, and optionally without the patientbeing present.
 14. A test apparatus configured for carrying out themethod as claimed in claim
 1. 15. A ventilator comprising the testapparatus as claimed in claim
 14. 16. The method of claim 1 whereinadjusting ventilator settings in the ventilated patient in need thereofis a manual adjustment.
 17. The method of claim 1 wherein adjustingventilator settings in the ventilated patient in need thereof is carriedout by a computer program which, when executed by a processor carriesout, adjustment of the ventilator settings based on the result of saidmeasurement of lung inhomogeneity.
 18. The method of claim 17 whereinadjusting ventilator settings occurs automatically.